Founder mutations in the LDL receptor gene contribute significantly to the familial hypercholesterolemia phenotype in the indigenous South African population of mixed ancestry.

The South African population harbors genes that are derived from varying degrees of admixture between indigenous groups and immigrants from Europe and the East. This study represents the first direct mutation-based attempt to determine the impact of admixture from other gene pools on the familial hypercholesterolemia (FH) phenotype in the recently founded Coloured population of South Africa, a people of mixed ancestry. A cohort of 236 apparently unrelated patients with clinical features of FH was screened for a common mutation causing familial defective apolipoprotein B-100 (FDB) and seven low-density lipoprotein receptor (LDLR) gene defects known to be relatively common in South Africans with FH. Six founder-type 'South African mutations' were responsible for FH in approximately 20% of the study population, while only 1 patient tested positive for the familial defective apolipoprotein B-100 mutation R3500Q. The detection of multiple founder-type LDLR gene mutations originating from European, Indian and Jewish populations provides direct genetic evidence that Caucasoid admixture contributes significantly to the apparently high prevalence of FH in South African patients of mixed ancestry. This study contributes to our knowledge of the biological history of this unique population and illustrates the potential consequences of recent admixture in populations with different disease risks.

A comparison of the metabolic effects of captopril and atenolol on glucose, insulin and lipoproteins in patients with mild-to-moderate essential hypertension.

The metabolic effects of captopril 25 mg twice daily and atenolol 50 mg daily on glucose, insulin and lipids were compared in 83 otherwise healthy mild-to-moderate hypertensive between the ages of 25 and 60 years in a randomised double-blind trial. Hourly glucose and insulin levels were measured during a 2-hour 75 g oral glucose tolerance test at baseline and after 12 weeks of treatment. Lipid profiles including total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, HDL2, HDL3, triglycerides, apoprotein (Apo)A1, ApoB, and Apo(a) were obtained before and after the treatment period. Blood pressure decreased significantly and equivalently in both treatment groups. The glucose and insulin levels and glucose x insulin product at 2 hours after the glucose load increased after 12 weeks of treatment with atenolol compared with the baseline values, but these parameters all decreased after the treatment period with captopril compared with their baseline values. These results indicate an improvement in insulin sensitivity with captopril and a deterioration with atenolol. HDL-cholesterol and HDL3 decreased in the atenolol group but increased in the captopril group. We conclude that captopril has more favourable effects than atenolol on glucose, insulin and lipid metabolism in the treatment of mild-to-moderate hypertension.

Free cholesterol concentrations in the high-density lipoprotein subfraction-3 as a risk indicator in patients with angiographically documented coronary artery disease.

BACKGROUND: The pathophysiology of plasma lipoprotein metabolism has long been linked to coronary artery disease (CAD). The present study evaluated the association between plasma lipoprotein lipid and apolipoprotein (apo) components and CAD in a group of 80 consecutive Caucasian patients undergoing coronary angiography. METHODS: Coronary cineangiography was carried out using the Judkins technique and the lesions quantified by calculating a coronary artery lesion score (CALS). Very low- and low-density lipoproteins (VLDL and LDL) were separated by ultracentrifugation, and high-density lipoprotein (HDL) and HDL subfraction-3 (HDL3) isolated by a differential precipitation procedure. Apo A-I, A-II, and B were assayed by endpoint laser nephelometry using specific antibodies. Total cholesterol, free cholesterol, and fatty acid concentrations were measured by gas-liquid chromatography, and lecithin: cholesterol acyltransferase (LCAT) activity by the decrease in the concentration of free cholesterol. RESULTS: On the basis of the presence of CAD, the 80 patients were divided into two groups: 52 (65%) with CAD (mean CALS = 7.8) and 28 (35%) without CAD (zero CALS). The lipoprotein fraction that most clearly differentiated the groups was HDL cholesterol concentration, with a mean +/- SEM value of 36.5 +/- 1.5 mg/dl for those with CAD and 45.1 +/- 2.1 mg/dl for those without (P < 0.01). The mean HDL3 cholesterol concentration was 29.9 +/- 1.2 mg/dl for patients with CAD and 37.4 +/- 1.8 mg/dl for those without (P < 0.001). These differences in HDL cholesterol and HDL3 cholesterol were mainly caused by differences in the free cholesterol component, with a mean HDL free cholesterol level of 10.8 +/- 1.1 and 16.1 +/- 1.4 mg/dl (P < 0.01), and a mean HDL3 free cholesterol level of 7.6 +/- 0.6 and 11.9 +/- 0.8 mg/dl (P < 0.001) in patients with and without CAD, respectively. Plasma LCAT activity was decreased in patients with CAD (P < 0.05), as were the apo A-I and A-II concentrations in both the HDL (P < 0.001) and HDL3 (P < 0.001) fractions. No significant association was found between CAD and HDL2 cholesterol or plasma total cholesterol, LDL cholesterol, or VLDL cholesterol concentrations. A stepwise discriminant analysis revealed that HDL3 free cholesterol was the only variable selected. Using HDL3 free cholesterol as a screening variable for CAD (cutoff 10.55 mg/dl), the sensitivity for CAD was 87% and the specificity for non-CAD 67%. The positive and negative predictive values of HDL3 free cholesterol were 82 and 75%, respectively. CONCLUSION: We have shown that the concentrations of HDL cholesterol and HDL3 most clearly differentiated between patients with and without CAD.

Simvastatin in non-insulin-dependent diabetic patients with hypercholesterolaemia.

The objective of this study was to evaluate the lipid-lowering effect of simvastatin in non-insulin-dependent diabetes mellitus (NIDDM) patients with hypercholesterolaemia while possible clinical and biochemical adverse effects were monitored for. Forty-three NIDDM patients with hypercholesterolaemia (total cholesterol > 6.5 mmol/l) used simvastatin after a detailed clinical laboratory evaluation as well as a 4-week wash-out period and a 4-week placebo baseline period. Simvastatin treatment was initiated with a 10 mg dose for 6 weeks; this was increased to 20 mg and 40 mg at 12 and 18 weeks of follow-up respectively if the total cholesterol level had not decreased to below 5.17 mmol/l. Patients were placed on a lipid-lowering diet and continued to take any regular non-lipid-lowering medication throughout the trial; side-effects were monitored at 6-week intervals until patients had taken simvastatin for 24 weeks. The mean total cholesterol level was reduced by 22.2% at the first follow-up visit, and by 24.2%, 23.3%, and 28.5% at the second, third and fourth follow-up visits respectively compared with base-line levels. A dose of 10 mg simvastatin brought about a reduction in total cholesterol similar to those found with higher doses. The mean triglyceride level was reduced by 20.9% with 20 mg simvastatin. The high-density lipoprotein cholesterol level was not altered significantly and neither was the control of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

The first 6 years of the Tygerberg Hospital lipid clinic.

The Tygerberg Hospital Lipid Clinic was established in July 1983. The demographic characteristics, lipid abnormalities, coronary risk factor profile, treatment status and 6-month follow-up lipid changes of patients seen during its first 6 years are summarised. During this period 329 patients were seen and complete lipograms were available for 312 of them. This patient population, consisting of 87.2% whites and 12.8% coloureds, represented a wide age range (2-69 years), various occupations and the whole spectrum of educational qualifications. The plasma cholesterol levels of 78.8% of the patients could be described as high risk, according to the cholesterol action limits of the Heart Foundation of Southern Africa, and 33.2% had low high-density lipoprotein cholesterol (less than 1 mmol/l) levels. Approximately 20% of the patients had familial hypercholesterolaemia and 31.1% were already on lipid-lowering medication before registration. The Lipid Clinic succeeded in improving the mean overall plasma cholesterol levels by 8% during the 6 months after registration and provided essential information for the planning of treatment strategies for patients with hypercholesterolaemia.

Progressive familial heart block type I. Clinical and pathological observations.

Progressive familial heart block type I (PFHB-I) is an autosomal inherited disease. It was previously postulated that the disease is limited to the cardiac conduction tissue. The presentation of a patient with dilated cardiomyopathy focused on the possibility that this might be part of PFHB-I. This observation led to routine echocardiographic examination of patients with complete heart block, who belonged to PFHB-I families, and another 5 cases with signs of dilated cardiomyopathy were identified. This is the first time, to our knowledge, that the histological picture of PFHB-I has been described. From these case reports it is clear that in the presence of a dilated cardiomyopathy the prognosis in PFHB-I tends to be poor.

A 6-month trial of simvastatin (HMG-CoA reductase inhibitor) in the treatment of hypercholesterolaemia.

The aim of this study was to evaluate the long-term efficacy and tolerability of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin, over a 24-week period. Patients (108) with primary hypercholesterolaemia were clinically, haematologically and biochemically evaluated and established on a cholesterol-lowering diet. After a wash-out period free from other lipid-lowering drugs and a baseline period on placebo of 1 month each, 10 mg simvastatin was introduced at night. The dose was increased to 20 mg and 40 mg at 6 and 12 weeks' follow-up respectively if the total cholesterol (TC) level was still above 5.17 mmol/l. Follow-up took place every 6 weeks and included lipid, haematological, biochemical and clinical evaluation. A full ophthalmological evaluation was conducted at baseline and at 24 weeks' follow-up. Overall the TC level was reduced below the baseline level by 34.3% at week 18 of follow-up and 32.5% at week 24. Patients with higher initial TC levels showed greater TC lowering in response to simvastatin than did those with lower initial TC levels. A group of 45 patients was followed up for an additional 12 weeks after the end of the trial and maintained TC reductions similar to those at the end of the trial. Fourteen patients experienced adverse effects which were thought to be drug-related. One patient was withdrawn from the trial after developing conjunctivitis that proved to be related to the use of simvastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Electron microscopic analysis of the specific granule content of human atria. An investigation of the role of atrial pressure and atrial rhythm in the release of atrial natriuretic peptide.

Knowledge about the stimulus for the release of atrial natriuretic peptide (ANP) from human atria is incomplete. Atrial stretch is known to be a stimulus and atrial tachyarrhythmias are thought to be another. The effects of atrial size (by two-dimensional echocardiography) and atrial fibrillation on the atrial specific granule content of human atria were studied to gain insight into the secretory mechanisms of ANP. An electron microscopic analysis of the atrial granule content was used to study 12 patients--5 with mitral stenosis and sinus rhythm, 3 with mitral stenosis and atrial fibrillation and 4 controls. Granules were counted using a free count and montage method. This is the first report of such a morphometric analysis in humans. Granule counts were significantly raised in the patients with mitral stenosis compared with controls (P less than 0.014). This observation probably reflects a high turnover state induced by elevated atrial pressures. Further support for this conclusion is provided by the demonstration of a positive correlation between granule counts and left atrial size (r = 0.86; P less than 0.01). The tendency for higher counts in patients with atrial fibrillation may be related to the rhythm disturbance itself, but clinical and echocardiographic data suggest more severe atrial pressure overload in this group.

[Primary echinococcus cyst of the heart. A case report]. / Primêre echinococcus-sist van die hart. N gevalbespreking.

A young male commercial pilot, completely asymptomatic of heart disease, was found to have an abnormal ECG on routine examination. This consisted of a bifascicular block (left anterior hemiblock plus a complete right bundle-branch block). Aviation regulations demanded further examination to rule out possible cardiac disease. On two occasions in 1984 and again in 1986 cardiac catheterisation was performed and revealed normal left ventricular function and normal coronary arteries. On 15 April 1986 an echocardiogram revealed a large cystic mass in the right ventricle, which was further delineated by right-sided cine-angiography. The patient was referred for cardiac surgery with the diagnosis of an Echinococcus cyst as the most likely possibility. Open-heart surgery was performed on 16 July 1986 and a 4 x 4 cm hydatid cyst, originating from the right ventricle septum and projecting into the right ventricular cavity, was removed. The diagnosis of Echinococcus granulosus was confirmed by histological examination.

Haplotypes identified by 10 DNA restriction fragment length polymorphisms at the human low density lipoprotein receptor gene locus.

Ten useful two allele restriction fragment length polymorphisms of the low density lipoprotein receptor gene were used for haplotype analysis in 45 unrelated familial hypercholesterolaemic (FH) patients, 60 normal controls, and 32 FH homozygotes, all of whom were white Afrikaners. Pedigree analysis in 27 informative heterozygous FH and 23 normal families has shown the segregation of at least 17 haplotypes in the normal population (111 chromosomes) compared to a predominant association of two of these haplotypes with the disease in the FH subjects. This association was further confirmed in 32 FH homozygotes, indicating at least two 'founder' members for the disease in the Afrikaner population. Recombination events were not detected in any of the families studied and we thus conclude that the haplotypes associated with FH function as specific markers for the disease and will allow presymptomatic diagnosis in affected families.

[The correlation between ECG characteristics and hemodynamic results in isolated atrial septal defects]. / Die korrelasie tussen EKG-eienskappe en hemodinamiese gevolge van geïsoleerde atriale septale defekte.

Electrocardiographic characteristics and haemodynamic findings in 30 patients with secundum atrial septal defects were correlated retrospectively to determine whether any haemodynamic deductions could be made based on ECG findings. Although statistically significant correlations were found, no accurate haemodynamic estimations could be made based on ECG findings.

Haplotype associations of three DNA polymorphisms at the human low density lipoprotein receptor gene locus in familial hypercholesterolaemia.

The frequency and inheritance of three restriction fragment length polymorphisms (RFLPs) of the low density lipoprotein (LDL) receptor gene were investigated in 27 South African families with familial hypercholesterolaemia. Four haplotypes, defined by the enzymes PvuII, StuI, and NcoI, were found to segregate in this population. The frequency of the rare allele detected by NcoI was found to be 0.53 in 45 unrelated familial hypercholesterolaemic (FH) patients compared to 0.33 in 60 normal controls (p less than 0.005). In 71% of the families studied, a haplotype with common alleles for PvuII and StuI and the rare allele for NcoI cosegregated with the defective gene. In 20% of the families, a second haplotype with rare alleles for PvuII and StuI and common allele for NcoI segregated with FH. In these families the haplotypes unambiguously cosegregate with the disease and can therefore be used for early diagnosis of FH.

Plasma vitamin A, E, C and B6 levels in myocardial infarction.

Vitamin A, E, C and B6 status was studied in 30 patients with myocardial infarction and in 19 age- and sex-matched patients after elective surgery or trauma. Plasma levels of the four vitamins studied were low, remained low or decreased transiently in both groups of patients during the acute catabolic response phase, and began to return to normal after the third day from the start of the catabolic response. These changes in plasma levels are therefore neither of any special pathophysiological importance in nor specific to myocardial infarction.

A DNA polymorphism in the human low-density lipoprotein receptor gene.

A new restriction fragment length polymorphism (RFLP) in the low-density lipoprotein receptor gene is described using the Stu I restriction endonuclease and a cDNA probe. The frequency of the two RFLP alleles was determined in 60 unrelated white subjects and 11.7% of them were found to be heterozygous for the polymorphism. Mendelian segregation of the RFLP was found in 3 informative families. The possible use of the RFLP in the diagnosis of familial hypercholesterolaemia in South Africa is discussed.

Late symptomatic exercise-induced coronary vasospasm after percutaneous transluminal coronary angioplasty. A case report and review.

A patient who underwent a successful double-vessel percutaneous transluminal coronary angioplasty (PTCA) had suffered from exercise-induced ST-segment elevation associated with angina pectoris (AP). This ECG pattern was present both before and 12 months after PTCA while nifedipine (Adalat; Bayer-Miles) therapy was electively discontinued. Reintroduction of calcium blockade with this drug eliminated the chest pain and resulted in normalization of the stress ECG. Cardiac catheterization at 6 and 12 months after PTCA demonstrated continuing angiographic improvement of the coronary stenoses of the left anterior descending and left circumflex (LCx) coronary arteries previously subjected to PTCA. It is believed that coronary artery spasm at the PTCA site on the LCx coronary artery was responsible for the AP and exercise-induced ST-segment elevation. Likely pathogenetic mechanisms of coronary vasospasm during and after the performance of PTCA, as well as the interrelationship with re-stenosis and the clinical implications of drug therapy, are discussed.

Effects of nifedipine on the peri-operative ECG, as determined by continuous Holter monitoring. A double-blind study.

A double-blind study was performed on 50 elderly patients undergoing hip-replacement surgery under general anaesthesia; 26 were given nifedipine and the remaining 24 placebo to determine effects on the continuously monitored (Holter) ECG during the 4 peri-operative days. Drugs were only administered during the latter 3 days of the observation period. Surgery was performed on the morning of the 3rd day. A striking feature was the high incidence of arrhythmias in both groups of patients, a finding previously documented in both 'normal' and elderly people. A decrease in ST-segment changes was expected in the nifedipine-treated patients. An unexpected finding, therefore, was the lack of protection against cardiac ischaemic changes in the nifedipine-treated patients compared with the placebo patients. Interpretation of the ST segment as seen in the Holter-monitored ECG remains controversial. We have no clear explanation for the lack of protection against ischaemic changes. The effects of profound vasodilatation produced by nifedipine in elderly patients subjected to major surgery, general anaesthesia including administration of enflurane, and a variable amount of blood loss in the postoperative period may be important factors. In conclusion, one should perhaps be cautious of nifedipine administration under these circumstances.

[The effect of heparin induced increase of free plasma thyroxine on cardiac rhythm after myocardial infarction]. / Die effek van heparien-geïnduseerde styging in vrye plasmatiroksien op die hartritme na miokardiale infarksie.

It is well known that an acute myocardial infarction is accompanied by a rise in levels of plasma free fatty acids (FFA), which may lead to a subsequent increase in cardiac arrhythmias. Administration of heparin to patients after an acute myocardial infarction gives rise to an increase both in plasma FFA levels and plasma free thyroxine levels. If administered without a fatty meal the rise in FFA is not accompanied by an increase in arrhythmias. The effect of the heparin-induced rise in plasma free thyroxine on cardiac rhythm has never been investigated. The aim of the present study was to investigate a possible arrhythmic effect of a heparin induced increase in plasma free thyroxine in a group of patients with acute myocardial infarction. We were able to confirm a significant heparin-induced rise in plasma free thyroxine levels, as measured by the effective thyroxine ratio. Although a slightly significant increase in ventricular premature beats could be demonstrated after heparin administration when using the Wilcoxon rank sum test for statistical analysis (but not when the paired t-test was utilized), no significant correlation with free thyroxine levels could be found. Heparin administration to patients suffering from myocardial infarction seems to be safe in terms of a possible arrhythmic effect.